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  • Perspective
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Gut microbiome immaturity and childhood acute lymphoblastic leukaemia

Nature Reviews Cancer volume 23, pages 565–576 (2023)Cite this article

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Abstract

Acute lymphoblastic leukaemia (ALL) is the most common cancer of childhood. Here, we map emerging evidence suggesting that children with ALL at the time of diagnosis may have a delayed maturation of the gut microbiome compared with healthy children. This finding may be associated with early-life epidemiological factors previously identified as risk indicators for childhood ALL, including caesarean section birth, diminished breast feeding and paucity of social contacts. The consistently observed deficiency in short-chain fatty-acid-producing bacterial taxa in children with ALL has the potential to promote dysregulated immune responses and to, ultimately, increase the risk of transformation of preleukaemic clones in response to common infectious triggers. These data endorse the concept that a microbiome deficit in early life may contribute to the development of the major subtypes of childhood ALL and encourage the notion of risk-reducing microbiome-targeted intervention in the future.

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Fig. 1: Early development of the gut microbiome in healthy children.
Fig. 2: Case–control studies investigating differences in gut microbiome diversity between children with newly diagnosed acute lymphoblastic leukaemia and healthy children.
Fig. 3: Case–control studies investigating differences in gut microbiome composition at the level of phylum and genus between healthy children and children with newly diagnosed acute lymphoblastic leukaemia.
Fig. 4: The two-hit model of childhood B cell precursor-acute lymphoblastic leukaemia.

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Data availability

The primary data that support the findings presented in this Perspective article, including the results of our re-analysis of participant-level data of the study of Liu et al.71, are available as Supplementary figures.

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Acknowledgements

The authors acknowledge support from the Cancer Research UK (CRM 171X), The Children’s Cancer and Leukaemia Group (CCLGA2019.02), The Royal Marsden Cancer Charity, the Wood family-in memory of Artemis and The Institute for Cancer Research, London.

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Authors and Affiliations

  1. Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK

    Ioannis Peppas, Anthony M. Ford, Caroline L. Furness & Mel F. Greaves

  2. Department of Paediatric Oncology, The Royal Marsden Hospital Sutton, Surrey, UK

    Ioannis Peppas & Caroline L. Furness

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  1. Ioannis Peppas
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  2. Anthony M. Ford
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  4. Mel F. Greaves
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The authors contributed equally to all aspects of the article.

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Correspondence to Mel F. Greaves.

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Supplementary information

Glossary

α-Diversity

A measure of the number of different taxa (richness) and/or the degree of evenness in their relative abundance within a single sample.

β-Diversity

A measure of the degree of similarity or distance between the composition of the microbial communities of two samples.

Activation-induced cytidine deaminase

(AID). An enzyme required for somatic hypermutation and class-switch recombination of immunoglobulin genes during B cell maturation and immune response.

Area under the receiver operating characteristic curve

(AUC). An aggregate measure of the performance of a predictive model across all possible classification thresholds.

Bray–Curtis dissimilarity

A measure of β-diversity that quantifies the degree of dissimilarity in the composition of the microbial communities of two samples.

Chao1

A measure of α-diversity that takes into account the number of different taxa (richness) within a sample.

Human milk oligosaccharides

(HMOs). Human milk oligosaccharides are unconjugated complex glycans that have a central role in the development of the gut microbiome–immune system axis.

High hyperdiploidy

A genetic aberration characterized by chromosomal gains (>51 chromosomes) that is commonly found in preleukaemic clones of childhood B cell precursor ALL.

Inverse Simpson index

A measure of α-diversity that takes into account both richness and evenness within a sample, giving more weight to common taxa.

Leptin

A hormone produced by adipose tissue that has a central role in the regulation of energy balance and has widespread effects in multiple organ systems, including haematopoietic cells.

Linear discriminant analysis of effect size

(LEfSe). Determines the taxa most likely to explain differences between study groups. It uses standard statistical tests to detect taxa with significant difference in relative abundance between the groups, as well as additional tests to assess the biological significance and relevance of these taxa.

Microorganism-associated molecular patterns

(MAMPs). Molecular structures conserved among classes of microorganisms that can be recognized by pattern recognition receptors to elicit immune responses.

Neonatal Guthrie cards

Samples of dried blood routinely collected after birth via heel prick for the purpose of universal screening for genetic conditions.

Peyer’s patches

Gut-associated lymphoid tissue found in the small intestine that forms the interface of the gut microbiome-mediated immune system priming.

Shannon diversity index

A measure of α-diversity that takes into account both richness and evenness of taxa within a sample, giving more weight to rare taxa.

Short-chain fatty acids

(SCFAs). Metabolites produced by gut commensals through the fermentation of non-digestible fibre.

Weighted Unifrac distance

A measure of β-diversity that incorporates abundance information and places more weight to common species. By contrast, the unweighted Unifrac distance is a measure of β-diversity that takes into account the presence and absence of taxa.

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Peppas, I., Ford, A.M., Furness, C.L. et al. Gut microbiome immaturity and childhood acute lymphoblastic leukaemia. Nat Rev Cancer 23, 565–576 (2023). https://doi.org/10.1038/s41568-023-00584-4

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